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Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

Research output: Contribution to journalArticlepeer-review

David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C. Macaulay, Hsin Jung Chou, Russell B. Fletcher, Diya Das, Kelly Street, Hector Roux de Bezieux, Yoon Gi Choi, Davide Risso, Sandrine Dudoit, Elizabeth Purdom, Jonathan Mill, Ralph Abi Hachem, Hiroaki Matsunami & 5 more Darren W. Logan, Bradley J. Goldstein, Matthew S. Grubb, John Ngai, Sandeep Robert Datta

Original languageEnglish
Article numberabc5801
Number of pages20
JournalScience Advances
Volume6
Issue number31
Early online date31 Jul 2020
DOIs
Accepted/In press18 Jun 2020
E-pub ahead of print31 Jul 2020
Published31 Jul 2020

Bibliographical note

Funding Information: S.R.D. was supported by grants RO11DC016222 and U19 NS112953 from the NIH and by the Simons Collaboration on the Global Brain, and the HMS Neurobiology Imaging Facility was supported by NIH grant P30NS072030. D.H.B. was supported by an NSF Graduate Research Fellowship. J.N. was supported by NIH grant RO1DC007235. D.R. was supported by Programma per Giovani Ricercatori Rita Levi Montalcini granted by the Italian Ministry of Education, University, and Research. K.V.d.B. is a postdoctoral fellow of the Belgian American Educational Foundation (BAEF) and was supported by the Research Foundation Flanders (FWO), grant 1246220N. D.D. was a fellow of the Berkeley Institute for Data Science, funded in part by the Gordon and Betty Moore Foundation (grant GBMF3834) and the Alfred P. Sloan Foundation (grant 2013-10-27). M.L. and M.S.G. were supported by a Leverhulme Trust Research Grant (RPG-2016-095) and a Consolidator Grant from the European Research Council (725729; FUNCOPLAN). J.M. was supported by a Medical Research Council grant (K013807) and a Medical Research Council Clinical Infrastructure Award (M008924). I.C.M. was supported by a BBSRC New Investigator Grant (BB/P022073/1) and the BBSRC National Capability in Genomics and Single Cell Analysis at Earlham Institute (BB/CCG1720/1). B.J.G. was supported by grant R01DC016859. H.M. was supported by grants R01DC014423 and R01DC016224. Publisher Copyright: © 2020 The Authors.

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Abstract

Altered olfactory function is a common symptom of COVID-19 (coronavirus disease 2019), but its etiology is unknown. A key question is whether SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2; CoV-2)-the causal agent in COVID-19-affects olfaction directly, by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, by perturbing support cells. Bulk and single-cell RNA sequencing revealed that support and stem cells in the human and mouse olfactory epithelium and vascular pericytes in the mouse olfactory bulb express angiotensin-converting enzyme 2 (ACE2), which is essential for CoV-2 cell entry. In contrast, ACE2 was not detected in either olfactory sensory neurons or olfactory bulb neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally located olfactory epithelial sustentacular cells and mouse olfactory bulb pericytes. These findings suggest that CoV-2 infection of non-neuronal cell types leads to olfactory dysfunction in patients with COVID-19.

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